Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile

摘要

A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNFIA) as a key regulator of fucosylation. We hypothesized that loss-of-function HNFIA mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNFIA-MODY. In a pilot comparison of 33 subjects with HNFIA-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfuco-sylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNFIA-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-M0DY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNFIA-MODY than in controls or other diabetes subtypes, offered good discrimination between HNFIA-MODY and both type 1 and type 2 diabetes (C statistic≥0.90), and enabled us to detect three previously undetected HNFIA mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNFIA-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNFIA dysfunction.